An opposing time‐dependent immune‐modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen–induced arthritis

Abstract

Objective. The sympathetic nervous system (SNS) seems to play a proinflammatory role in the early asymptomatic phase of arthritis, but its role in the late stages of chronic arthritis is not well known. The purpose of this study was to examine the effects of the SNS on late-stage chronic arthritis in mice with type II collagen-induced arthritis (CIA).Methods. We tested the effects of the SNS by ablating sympathetic nerves at different time points in mice with CIA. Early sympathectomy was performed 7 days before immunization. Late sympathectomy was performed on day 56. Cytokine stimulation assays were performed on local lymph node cells and spleen cells, and levels of interleukin-10 (IL-10), IL-4, tumor necrosis factor ␣ (TNF␣), and interferon-␥ (IFN␥) were determined.Results. Animals with CIA that underwent early sympathectomy showed significantly lower arthritis scores than the controls. In contrast, animals that underwent late sympathectomy had significantly increased arthritis scores compared with controls. On day 0, lymph node cells from animals subjected to early sympathectomy had increased levels of IL-10 and IL-4 and unchanged levels of TNF␣ and IFN␥ compared with those from untreated animals. This indicates an immune-stimulating property of the SNS in draining lymph nodes. On day 80, lymph node cells and spleen cells from animals subjected to late sympathectomy showed increased levels of TNF␣ and IFN␥ compared with those from nonsympathectomized controls with CIA. This indicates an immune-depressing property of the SNS in draining lymph nodes and spleen. Arthritis per se largely diminished sympathetic nerve fiber density in synovium on day 80 (P < 0.01).Conclusion. The effect of the SNS is bimodal, enhancing or depressing levels of proinflammatory and antiinflammatory cytokines. This feature is dependent on the time point of immune system activation and the respective compartment. The SNS supports inflammation during the asymptomatic phase of CIA, whereas it inhibits inflammation during the chronic symptomatic phase.Since the work of Selye in the 1940s (1), the sympathetic nervous system (SNS) together with the hypothalamic-pituitary-adrenal axis has been thought to play an important supportive role in the fight-or-flight response during stressful events. In linking this important concept to inflammatory diseases, several groups of investigators working from 1960 to the late 1980s delineated a proinflammatory role of the SNS for the early inflammatory response (for review, see ref.2). Indeed, the SNS seems to be a critical proinflammatory component of neurogenic inflammation, which is particularly evident during the first hours after induction of joint inflammation (3), when the SNS mediates an increase in vessel leakage, plasma extravasation, migration of leukocytes to inflamed tissue. This is accompanied by stimulation of sensory nerve fibers (2).At the beginning of the 1980s, with the introduction of in vitro immune cell culture assays that could continue for several days and with the detection of Sup...

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature

“…Second, we were unable to identify a particular nerve quality required for K/BxN serum-transferred arthritis. This finding contrasts with previous reports of an effect of manipulating the SNS in other mouse models of inflammatory arthritis (sometimes via the same inhibitors) (3,15). A likely explanation for the divergent results is that the models previously interrogated are rather different: Unlike the K/BxN serum-transfer system, they encompass both the initiation and effector stages of arthritis and depend on the injection of an adjuvant to induce disease.…”

“…The SNS seems to exert pro-or anti-inflammatory activity depending on the context, typically promoting inflammation at the outset of an immune response and reining it in at later stages (14). For example, blockade of β2 sympathetic signaling delayed the onset of antigen-induced arthritis and reduced its severity (3), whereas sympathectomy performed late in the course of collagen-induced arthritis worsened disease manifestations (15). To test the influence of the SNS in the K/BxN serum-transfer system, we administered, along with the serum, a set of pharmacologic agents that operate by a diversity of mechanisms.…”

Disrupted brain–immune system–joint communication during experimental arthritis

“…Thus, CII-induced arthritis in DA rats appears to be a suitable model with which to analyze the mechanisms that interfere with the activation of the HPA axis during arthritis, a defect that is not observed during other experimentally induced inflammatory/autoimmune diseases, such as experimental autoimmune encephalomyelitis (28,32,33). Furthermore, it has been shown that the density of noradrenergic nerve fibers is reduced in the inflamed joints of RA patients (34) and in mice with CII-induced arthritis (2), and this finding was confirmed in our studies of the rat model. Sympathetic denervation could be related to local activation of immune cells, since we have reported a similar reduction in the density of noradrenergic fibers in lymphoid organs of mice in which an autoimmune/lymphoproliferative disease develops spontaneously (35).…”

“…Cryosections were immunostained with primary antibodies against tyrosine hydroxylase (Chemicon, Temecula, CA), the key enzyme of NA synthesis in sympathetic nerve endings, according to the protocol described elsewhere (7). The numbers of stained nerve fibers with a minimum length of 50 m (indicated by a small-micrometer eyepiece) were counted in selected fields at 400ϫ magnification, as recently described (2). At least 4 rats were examined at each time point.…”

“…The inflammatory component of the disease can be modulated at the level of the joints by efferent peripheral nerves (2,(4)(5)(6), and the SNS seems to exert a proinflammatory influence during the induction, asymptomatic phase but an antiinflammatory effect in the late symptomatic phase of type II collagen-induced arthritis (2). Interestingly, sympathetic innervation is largely decreased in advanced stages of type II collagen-induced arthritis in mice, so that the antiinflammatory influence of sympathetic nerve fibers might be missing during the symptomatic phase (2). Similar findings have been reported in patients with rheumatoid arthritis (RA) (7), a condition that is additionally complicated by low levels of endogenous cortisol (8).…”